The long term goal of the proposed research is to understand the mechanisms by which solar ultraviolet (UV) irradiation damages human skin and causes squamous cell skin cancer. UV irradiation from the sun is among the most common and harmful forms of environmental insult to human skin, the largest organ that is directly exposed to the environment. Epidemiological studies worldwide have established a direct connection between the incidence of squamous cell skin cancer and exposure to solar UV irradiation. Skin cancer is the most common type of cancer in the Caucasian population of the United States, with more than 500,000 to 1,000,000 cases diagnosed each year. The annual cost of treatment in the U.S. is estimated to be between $500 million and $1 billion. Therefore, skin cancer is a serious public health issue. Understanding molecular mechanisms by which solar UV irradiation damages skin and causes skin cancer will lead to more efficient prevention and treatment. UV irradiation is detrimental to human skin via two primary mechanisms: 1) altering DNA, which results in genetic mutations that can lead to cellular transformation, and 2) activation of a variety of signal transduction pathways, which ultimately up- regulate gene products that damage skin and promote an environment conductive to cancer formation. Accumulating evidence indicates that epidermal growth factor receptor (EGFR) plays pivotal roles in skin tumorigenesis and is a primary driving force by which UV irradiation stimulates signal transduction pathways that are harmful to the skin. Our previous studies have demonstrated that UV irradiation activates EGFR by oxidative inhibition of receptor-type protein tyrosine phosphatase-kappa (RPTPK), a specific negative regulator of EGFR. The focus of this proposal is to investigate regulation and function of RPTPK. The proposed studies will test the hypothesis that down-regulation of RPTPK leads to over-activation of EGFR, which promotes squamous cell skin cancer formation. Four Specific Aims are proposed: 1) examine the role of RPTPK in UV irradiation-induced inflammation and epidermal hyperplasia in transgenic mice, 2) investigate transcriptional regulation of RPTPK, 3) characterize UV irradiation-induced RPTPK oxidation in human skin in vivo, and 4) determine tumor suppressor property of RPTPK in cancer cell lines and mouse xenograft models. PUBLIC HEALTH RELEVANCE: Ultraviolet (UV) irradiation from the sun is one of the most common and harmful environmental factors to human skin. Chronic sun exposure causes premature skin aging and skin cancer, which is the most prevalent type of human cancer. The epidermal growth factor receptor (EGFR) has been demonstrated to play a central role in UV irradiation-induced skin damage. We have discovered that receptor type protein tyrosine phosphatase kappa (RPTPK) is a key regulator of EGFR function, and that RPTPK is inhibited by UV irradiation, in human skin in vivo. We hypothesize that this reduction of RPTPK leads to over- activation of EGFR with consequent skin damage. Our proposed studies will investigate molecular mechanisms that regulate RPTPK gene expression and enzymatic activity and the ability of RPTPK to function as a tumor suppressor. Information from our studies will provide a foundation for improved prognostic markers and chemoprevention strategies for skin cancer.